1. In vivo and in vitro evaluations of intestinal gabapentin absorption: effect of dose and inhibitors on carrier-mediated transport.
- Author
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Larsen MS, Frølund S, Nøhr MK, Nielsen CU, Garmer M, Kreilgaard M, and Holm R
- Subjects
- Administration, Oral, Amines blood, Amino Acids, Cyclic pharmacology, Animals, Caco-2 Cells, Cyclohexanecarboxylic Acids blood, Dose-Response Relationship, Drug, Gabapentin, Humans, Injections, Intravenous, Male, Membrane Transport Modulators pharmacology, Membrane Transport Proteins adverse effects, Models, Biological, Rats, Sprague-Dawley, gamma-Aminobutyric Acid blood, Amines administration & dosage, Amines pharmacokinetics, Cyclohexanecarboxylic Acids administration & dosage, Cyclohexanecarboxylic Acids pharmacokinetics, Intestinal Absorption drug effects, Intestinal Mucosa metabolism, Membrane Transport Proteins metabolism, gamma-Aminobutyric Acid administration & dosage, gamma-Aminobutyric Acid pharmacokinetics
- Abstract
Purpose: Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations, Methods: Pharmacokinetic parameters were determined following a range of intravenous (5-100 mg/kg) and oral doses (10-200 mg/kg) in rats. Transepithelial transport (50 μM-50 mM) and apical uptake of gabapentin (0.01-50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b(0,+)-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro., Results: Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine., Conclusions: The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.
- Published
- 2015
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